National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 2, 2010 • Volume 7 / Number 21

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A Closer Look

Engineering Progress against a Rare Cancer

An MRI scan of a 17-year-old male showing a chordoma extending from the nasal cavity to the brainstem. (Image courtesy of S Hassan, JM Abdullah, SJ Wan Din, and Z Idris) An MRI scan of a 17-year-old male showing a chordoma extending from the nasal cavity to the brainstem. (Image courtesy of S Hassan, JM Abdullah, SJ Wan Din, and Z Idris)

In 2006, during his freshman year at Duke University, Josh Sommer learned that the persistent headaches he was experiencing were caused by a tumor pressing on his brain stem. When surgeons removed the tumor, tests showed that it was a rare bone cancer known as chordoma. Just days after the procedure, Sommer began to download and read on his laptop computer every chordoma study he could access through the Duke library.

Unfortunately, he learned that patients with the disease live, on average, only 7 years after diagnosis. Chordomas can occur anywhere along the spinal column, from the base of the skull to the tailbone. Most chordomas grow slowly, but they are usually fatal. The 300 or so people who are diagnosed with the disease in the United States each year have few treatment options beyond surgery and radiation.

When Sommer returned to school in the fall, he was determined to help find a cure for his disease. In addition to his engineering classes, he joined the lab of Dr. Michael Kelley, a cancer researcher who, along with colleagues at NCI, had begun to look for chordoma genes in high-risk families. Sommer joined the ongoing effort to identify genetic regions of interest by profiling the activity of a gene that experts suspected might play a role in chordoma. The gene is called T, or Brachyury (for the protein it encodes—a transcription factor that regulates the activity of other genes).

But the evidence tying the gene to the disease was preliminary, and Sommer began to wonder whether his research would make a difference. “I remember riding my bike to the lab—sometimes in the rain—and thinking, is this really how I should be spending my time?” he recalled recently.

Four years later, his doubts are gone. There is growing evidence that the Brachyury/T gene may play a role not only in chordoma but also in other cancers as well. Sommer, now 22 years old and on leave from Duke, has dedicated himself to improving the lives of patients with chordoma. He recently became executive director of the Chordoma Foundation, an organization he co-founded in 2007 with his mother, Dr. Simone Sommer, to accelerate research on the disease.

A Duplicated Gene

Researchers know that chordomas arise from remnants of the notochord, which is an embryonic precursor to the spinal cord. The Brachyury/T gene regulates the development of the notochord in embryonic cells and is expressed in virtually all chordomas but not in most normal adult tissues.

The abnormal expression of the Brachyury/T gene in chordoma appears to be associated with the presence of extra copies of the gene. The most recent evidence comes from a report published last month showing that extra copies of the gene are common in chordoma tissue from patients with noninherited, or sporadic, forms of the disease.

This finding, by Dr. Adrienne Flanagan of University College London and her colleagues, is consistent with a study published last year that found extra copies of the gene in the germline DNA of patients with the familial or inherited form of the disease.

“Together, these results support a major role for changes to the Brachyury/T gene in the development of chordoma,” said Dr. Rose Yang of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). Dr. Yang was first author of the familial chordoma study, a long-term study of high-risk families co-led by Dr. Dilys Parry of DCEG and carried out in collaboration with Dr. Kelley’s lab at Duke.

Dr. Yang pointed out another similarity between the studies: each found higher levels of the brachyury protein even in some patients who did not have extra copies of the gene itself. “This highlights the need to identify mutations in other genes or an as-yet-unknown mechanism for improperly activating the production of brachyury in both familial and sporadic chordoma,” she noted.

Josh Sommer working in Dr. Michael Kelley’s laboratory at Duke University Josh Sommer working in Dr. Michael Kelley’s laboratory at Duke University

Exploring a Cancer Vaccine

Brachyury is also the focus of an effort under way at NCI to develop a cancer vaccine for patients with common cancers such as lung, breast, and colorectal. The Brachyury/T gene may be improperly switched on in these cancers, and cells expressing this protein could potentially be recognized and targeted by human immune cells, Dr. Claudia Palena of NCI’s Center for Cancer Research (CCR) and her colleagues said in a study published a few years ago.

More recently, the researchers reported that the Brachyury/T gene may promote a process known as the epithelial-mesenchymal transition in cancer cells, which makes them more invasive and better able to spread. The idea behind the vaccine would be “to stop this process in its tracks,” said Dr. Jeffrey Schlom of CCR’s Laboratory of Tumor Immunology and Biology, who is leading the project.

A phase I clinical trial to establish the safety and proper dose of the experimental vaccine could begin within a year. Although preliminary, “the work represents a nice example of developing a potential treatment for common cancers that could be applicable to rare cancers,” said Dr. Schlom.

In the Kelley lab at Duke, the work on the Brachyury/T gene started when Sommer undertook a project to characterize tumor cell lines that were said to be derived from chordoma. But the researchers soon learned that several cell lines published as being chordoma clearly were not. (A manuscript with the results is under review.) 

“The positive outcome of this work, which Josh was instrumental in advancing, is that there are now two cell lines that are well characterized as being derived from chordomas and may be useful models,” said Dr. Kelley. “The work on Brachyury began as part of his work on those cell lines and has now broadened significantly, both in our lab and others.”

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Overcoming Barriers to Research

During his time in the lab, Sommer saw firsthand the challenges of trying to study a rare disease. Critical resources, such as cell lines, tissue samples, and animal models, were scarce or did not exist. Nor was it clear who else was studying chordoma and, therefore, could be potential collaborators. “After some initial progress, we were hitting a wall,” Sommer recalled.

The Chordoma Foundation aims to overcome those barriers by building networks of researchers, funding the development of research tools and treatments, and creating ways for researchers to share their results as soon as possible. The hope is that potentially life-saving results could be shared almost in real time, rather than waiting months or years for publication in a medical journal, as often happens now.

“The biggest challenge with chordoma is the rarity of the disease,” said Dr. Paul Meltzer of CCR and a member of the Chordoma Foundation’s board of scientific advisers. “I work on a lot of uncommon cancers, and this is one of the rarest. It’s hard to study something when you can’t get tissue samples or reagents. You also need to get cooperation among the centers that see patients so that researchers can talk and share results.” Dr. Meltzer has seen patient-driven advocacy organizations for less-common cancers “spring up from time to time,” and the Chordoma Foundation is one of the most effective efforts he’s seen.

“Josh is an incredibly talented young man who has used his abilities to push for research on chordoma and hopefully new therapies,” said Dr. Meltzer. “He brought the disease to the attention of people at the highest levels of cancer research who wouldn’t have heard of it otherwise. He has a real chance of helping the chordoma field and patients with this disease.”

Bringing Researchers Together

Over the past 3 years, the Chordoma Foundation has brought together more than 100 investigators for two international scientific conferences. The Foundation has also funded research in seven labs and developed a research roadmap that “will ultimately lead us to the point of having a really good shot at curing this disease,” said Sommer. 

The Chordoma Foundation has helped the field in a number of ways, said Dr. Kelley. “The foundation was instrumental in stimulating more interaction among investigators who had not previously been communicating with one another. This led to new collaborations and the sharing of data.” The foundation also provides useful information about the disease and treatment options for patients and families, he added.

Among the researchers supported by the foundation is Dr. Vijaya Ramesh of Massachusetts General Hospital, whose lab studied several rare cancers, but not chordoma. After she published findings related to chordoma, however, Dr. Simone Sommer contacted her, and she is now collaborating on a project to develop a mouse model for the disease.

“The foundation pushed us researchers to all think about the disease together, and I’m happy to have been involved,” said Dr. Ramesh. But she was also realistic about the future: “Whether we can move this research forward really depends on what we learn from the mouse models and whether there is additional funding.”

Josh Sommer has been free of tumors for 4 years, and he goes back to the hospital for scans every 6 months. “For the most part, I’m able to put my disease out of my head and really focus on the job at hand,” he said. “But it hits home when I hear from patients who are struggling with the disease or about patients having a recurrence who are just being ravaged by this disease.

“Their stories are constant motivation to work as hard as possible and do everything we can to bring researchers together and to raise the funds to make the research happen,” he added.

—Edward R. Winstead and Sarah Curry

See also: Duplicated Gene May Explain Rare Cancer in Some Families

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